Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Exp Med. May 20, 2017; 7(2): 49-57
Published online May 20, 2017. doi: 10.5493/wjem.v7.i2.49
Role of LIGHT in the pathogenesis of joint destruction in rheumatoid arthritis
Afsie Sabokbar, Sara Afrough, David J Mahoney, Yoshinobu Uchihara, Catherine Swales, Nicholas A Athanasou
Afsie Sabokbar, Sara Afrough, David J Mahoney, Yoshinobu Uchihara, Catherine Swales, Nicholas A Athanasou, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford OX3 7HE, United Kingdom
Author contributions: All authors contributed equally to this work; Sabokbar A, Mahoney DJ and Uchihara Y performed the research; Swales C contributed clinical materials; Sabokbar A, Afrough S, Mahoney DJ, Uchihara Y and Athanasou NA analysed the data; Sabokbar A, Afrough S, Mahoney DJ and Athanasou NA wrote the paper and approved the final version of the article to be published.
Supported by the Rosetrees Trust, No. 242; and Arthritis Research Campaign (United Kingdom), No. 18358.
Institutional review board statement: All synovial studies and synovial fluid samples were taken from patients after informed consent and ethical permission was obtained for participation in this study. The research Ethics were granted by National Research Ethics Committee (Oxfordshire), REC reference number C01.070.
Institutional animal care and use committee statement: Not applicable.
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nicholas A Athanasou, MD, PhD, FRC (Path), Professor of Musculoskeletal Pathology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Windmill Rd, Oxford OX3 7HE, United Kingdom. nick.athanasou@ndorms.ox.ac.uk
Telephone: +44-1865-738136 Fax: +44-1865-738140
Received: January 26, 2017
Peer-review started: February 8, 2017
First decision: March 8, 2017
Revised: April 26, 2017
Accepted: May 3, 2017
Article in press: May 5, 2017
Published online: May 20, 2017
Processing time: 115 Days and 22.5 Hours
Abstract
AIM

To characterise the role of substitutes for receptor-activator nuclear factor kappa-B ligand (RANKL) in rheumatoid arthritis (RA) joint destruction.

METHODS

Synovial fluid (SF) macrophages isolated from the knee joint of RA patients were incubated with 25 ng/mL macrophage-colony stimulating factor (M-CSF) and 50 ng/mL LIGHT (lymphotoxin-like, exhibits inducible expression and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) in the presence and absence of 25 ng/mL RANKL and 100 ng/mL osteoprotegerin (OPG) on glass coverslips and dentine slices. Osteoclastogenesis was assessed by the formation of multinucleated cells (MNCs) expressing tartrate-resistant acid phosphatase (TRAP) on coverslips and the extent of lacunar resorption pit formation on dentine slices. The concentration of LIGHT in RA and osteoarthritis (OA) synovial fluid was measured by an enzyme-linked immunosorbent assay (ELISA) and the expression of LIGHT in RA and OA synovium was determined by immunohistochemistry using an indirect immunoperoxidase technique.

RESULTS

In cultures of RA SF macrophages treated with LIGHT and M-CSF, there was significant formation of TRAP + MNCs on coverslips and extensive lacunar resorption pit formation on dentine slices. SF-macrophage-osteoclast differentiation was not inhibited by the addition of OPG, a decoy receptor for RANKL. Resorption pits were smaller and less confluent than in RANKL-treated cultures but the overall percentage area of the dentine slice resorbed was comparable in LIGHT- and RANKL-treated cultures. LIGHT significantly stimulated RANKL-induced lacunar resorption compared with RA SF macrophages treated with either RANKL or LIGHT alone. LIGHT was strongly expressed by synovial lining cells, subintimal macrophages and endothelial cells in RA synovium and the concentration of LIGHT was much higher in RA compared with OA SF.

CONCLUSION

LIGHT is highly expressed in RA synovium and SF, stimulates RANKL-independent/dependent osteoclastogenesis from SF macrophages and may contribute to marginal erosion formation.

Keywords: Receptor-activator nuclear factor kappa-B ligand; Osteoclast; Rheumatoid arthritis; Resorption; LIGHT

Core tip: Rheumatoid arthritis (RA) is an inflammatory joint condition characterised by the formation of marginal erosions due to the activity of bone resorbing osteoclasts. Osteoclasts can be formed from macrophages by both receptor-activator nuclear factor kappa-B ligand (RANKL)-dependent and RANKL-independent mechanisms. LIGHT is a potent RANKL substitute that induces significant osteoclast formation from cultures of RA synovial fluid macrophages; this results in comparable levels of resorption to that seen in RANKL-treated cultures. LIGHT also stimulated RANKL-mediated lacunar resorption. LIGHT is highly expressed in RA joints and synovial fluid and is likely to play a key role in the pathogenesis of marginal erosion formation in RA.